TY - JOUR

T1 - Myocardial structural, contractile and electrophysiological changes in the guinea-pig heart failure model induced by chronic sympathetic activation

AU - Soltysinska, Ewa

AU - Osadchiy, Oleg

AU - Olesen, Søren-Peter

PY - 2011

Y1 - 2011

N2 - Widely used murine models of adrenergic-induced cardiomyopathy offer little insight into electrical derangements seen in human heart failure owing to profound differences in the characteristics of ventricular repolarization in mice and rats compared with humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant heart failure phenotype in the guinea-pig, an animal species whose ventricular action potential shape and restitution properties resemble those determined in humans. Isoprenaline (ISO), a ß-adrenoceptor agonist, was infused at variable dosage and duration using either subcutaneously implanted osmotic minipumps or daily injections, in an attempt to establish the relevant treatment protocol. We found that 3 months of daily ISO injections (final dose of 1 mg kg(-1), i.p.) promote heart failure evidenced by cardiac hypertrophy [increased cardiac weights, left ventricular (LV) posterior wall thickness, myocyte cross-sectional area and LV protein content], cardiac dilatation (increased LV internal diameters), basal systolic dysfunction (reduced LV fractional shortening determined by echocardiography and flattened LV systolic pressure-volume and stress-strain relationships assessed in isolated, perfused heart preparations), reduced contractile reserve in the presence of acute ß-adrenoceptor stimulation, and pulmonary oedema (increased lung weights). These changes were associated with prolongation of LV epicardial action potential, effective refractory period and QT interval, an upward shift of the electrical restitution curve determined over a wide range of diastolic intervals, and reduced maximal restitution slope. The physiological right ventricular-to-LV difference in action potential duration was eliminated in ISO-treated hearts, thereby contributing to impaired activation-to-repolarization coupling and reversed right ventricular-to-LV difference in repolarization time. In summary, we establish the guinea-pig model of ISO-induced cardiomyopathy, which enables the correlation of detrimental structural and contractile changes with repolarization abnormalities typically seen in human heart failure.

AB - Widely used murine models of adrenergic-induced cardiomyopathy offer little insight into electrical derangements seen in human heart failure owing to profound differences in the characteristics of ventricular repolarization in mice and rats compared with humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant heart failure phenotype in the guinea-pig, an animal species whose ventricular action potential shape and restitution properties resemble those determined in humans. Isoprenaline (ISO), a ß-adrenoceptor agonist, was infused at variable dosage and duration using either subcutaneously implanted osmotic minipumps or daily injections, in an attempt to establish the relevant treatment protocol. We found that 3 months of daily ISO injections (final dose of 1 mg kg(-1), i.p.) promote heart failure evidenced by cardiac hypertrophy [increased cardiac weights, left ventricular (LV) posterior wall thickness, myocyte cross-sectional area and LV protein content], cardiac dilatation (increased LV internal diameters), basal systolic dysfunction (reduced LV fractional shortening determined by echocardiography and flattened LV systolic pressure-volume and stress-strain relationships assessed in isolated, perfused heart preparations), reduced contractile reserve in the presence of acute ß-adrenoceptor stimulation, and pulmonary oedema (increased lung weights). These changes were associated with prolongation of LV epicardial action potential, effective refractory period and QT interval, an upward shift of the electrical restitution curve determined over a wide range of diastolic intervals, and reduced maximal restitution slope. The physiological right ventricular-to-LV difference in action potential duration was eliminated in ISO-treated hearts, thereby contributing to impaired activation-to-repolarization coupling and reversed right ventricular-to-LV difference in repolarization time. In summary, we establish the guinea-pig model of ISO-induced cardiomyopathy, which enables the correlation of detrimental structural and contractile changes with repolarization abnormalities typically seen in human heart failure.

KW - Action Potentials

KW - Adrenergic beta-Agonists

KW - Animals

KW - Cardiomyopathies

KW - Disease Models, Animal

KW - Guinea Pigs

KW - Heart Failure

KW - Isoproterenol

KW - Male

KW - Myocardial Contraction

KW - Myocardium

KW - Perfusion

KW - Receptors, Adrenergic, beta

KW - Ventricular Function, Left

KW - Ventricular Remodeling

U2 - 10.1113/expphysiol.2011.058503

DO - 10.1113/expphysiol.2011.058503

M3 - Journal article

C2 - 21571815

VL - 96

SP - 647

EP - 663

JO - Experimental Physiology

JF - Experimental Physiology

SN - 0958-0670

IS - 7

ER -